可对接PAD4活性口袋扰乱肿瘤细胞自噬的精氨酸衍生物的构效关系研究

PAD4 is markedly overexpressed in a majority of human cancers which makes PAD4 inhibitor high selective. And the PAD4 inhibitor is of lower toxicity for the indirect effect on DNA. In addition, PAD4 inhibitors control the expression of the tumor suppressor gene to promote cell differentiation and lead tumor cells to death by disturbing macrophages in tumor cells, which is just like switching the internal cell signals from growth to death. So novel PAD4 inhibitor discovery on this putative target for cancer treatment is the aim in this project. On the basis of YW3-56 structure in the patent, 4 series of aim compounds were modified and prepared. In vitro and in vivo anti-tumor bioassays and PAD4 inhibition are to be tested. Then molecular mechanism of PAD4 inhibition is to be explored. After that, the relationship between three modified groups of YW3-56 structure and activities should be studied to figure out the SAR of PAD4 inhibitors. Finally, 1-2 PAD4 inhibitors will be found to enter preclinical studies. Therefore, not only the selectivity problem, the critical issue of existing anticancer drugs, will be solved, but also the toxicity of anticancer drugs targeting DNA. The bioavailability will be improved and new anticancer drug strategy will be provided, which suggests that PAD4 inhibitor will be of significant application.

PAD4在肿瘤细胞的过表达使PAD4抑制剂选择性高；且因PAD4抑制剂不作用于DNA而显示毒性低的特点；此外它控制抑癌基因的表达、促进细胞分化，且扰乱肿瘤细胞的自噬，就像打开了肿瘤细胞死亡的开关，引起肿瘤细胞死亡。本项目针对抗肿瘤这一新靶点寻找PAD4抑制剂。在申请者具有知识产权的PAD4抑制剂YW3-56的结构上进行修饰，拟合成4个系列目标化合物；评价它们体内外抗肿瘤活性和抑制PAD4活性；探索抑制PAD4的分子机制；确定构成PAD4抑制剂三部分的结构修饰策略与活性之间的关系，为PAD4抑制剂研究提供构效关系；因此，本项目不仅解决现有抗肿瘤药物选择性差这一关键问题，还可回避针对DNA的抗肿瘤药物的毒性问题，为抗肿瘤药物研究提供了新的策略，具有显著的应用前景。

本项目针对抗肿瘤这一新靶点寻找PAD4 抑制剂。PAD4在肿瘤细胞的过表达使PAD4抑制剂选择性高;且因PAD4抑制剂不作用于DNA而显示毒 性低的特点;此外它控制抑癌基因的表达、促进细胞分化，其抑制剂就像打开了肿瘤细胞死亡的开关，引起肿瘤细胞死亡。在申请者具有知识产权的PAD4抑制剂YW3-56的结构上进行修饰，合成了4个系列共150个目标化合物，优化了合成工艺，合成条件中将 DCC 替代 EDCI，有机碱用 NMM 替换，DMF 替换为 THF，产率提高到 90%，成本降低，具有工业化应用前景；评价它们体内外抗肿瘤活性和抑制PAD4活性，探索抑制PAD4的分子机制，体外筛选出6个化合物（抑制PAD4酶的IC50为1.1~12.3 uM/L）;荷S180瘤小鼠的体内活性实验筛选发现在2 umol/Kg的剂量下有三个化合物的抑瘤率在45%~56%之间;再通过计算机辅助药物设计的工作站，再次确定了构成PAD4抑制剂三部分的结构修饰策略与活性之间的关系，为PAD4抑制剂研究提供构效关系;因此，本项目不仅解决现有抗肿瘤药物选择性差这一关键问题，还可回避针对DNA 的抗肿瘤药物的毒性问题，为抗肿瘤药物研究提供了新的策略，具有应用前景。